The differential protection of functional groups of similar reactivity is a major challenge for the synthesis of complex natural products. The task of distinguishing specific hydroxyl and amino functionalities becomes particularly daunting in carbohydrate chemistry when highly branched structures call for several selectively removable masking groups. Over the years a host of protecting groups has been introduced, each making use of the unique reactivity of the particular masking moiety. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; John Wiley & Sons; New York, 1999. Traditionally, benzyl ethers have been employed for ‘permanent’ protection and are removed during the late stages of the synthesis, while ester moieties and silyl ethers are used to ‘temporarily’ mask hydroxyl groups to be unveiled during the synthesis. Orthogonality of protecting groups, or the ability to remove one particular masking entity without affecting the others, is a key issue for synthetic planning and experimental execution.
The reactivity of benzyl ethers has been tuned by using substituted benzyl ether protecting groups which could be selectively removed in the presence of unsubstituted benzyl ethers. These substituted benzyl ethers were generally less stable to reaction conditions than unsubstituted benzyl ethers. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; John Wiley & Sons; New York, 1999, p 86–113. The 4-O-methoxy benzyl group (PMB) has found frequent applications in natural product synthesis since it can be cleaved oxidatively thus sparing most other protective groups. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; John Wiley & Sons; New York, 1999, p 86–91. The acid sensitivity of this group has somewhat restricted its synthetic utility. More recently, other 4-O-substituted benzyl ethers containing acetate and silyl substituents have been reported. Jobron, L.; Hindsgaul, O. J. Am. Chem. Soc. 1999, 121, 5835–5836. While these benzyl ether groups do not require palladium catalyzed hydrogenation for their removal, they necessitate treatment with base or fluoride respectively, followed by oxidative cleavage. These deprotection protocols forfeit compatibility of these 4-substituted benzyl ethers with ester, silyl, or PMB protecting groups.